1. Field of the Invention
The present invention relates to a screening system and method for automatically carrying out biochemical, cell biological or molecular biological analyses of liquids at the surfaces of a multiplicity of optical sensors/biosensors which are located in standardized multiwell plates (or other types of multi-vessel systems such as bars, strips, slides, rotor cuvettes etc. . . . ).
2. Description of Related Art
Today there is considerable interest in developing a screening system which can automatically carry out biochemical, cell biological or molecular biological analyses of liquids at the surfaces of a multiplicity of optical sensors/biosensors (or at least on parts of the surfaces of those optical sensors/biosensors) located in standardized multiwell plates (or other multi-vessel systems such as bars, strips, slides, rotor cuvettes etc. . . . ). The targeted analyses often include drug discovery, drug screening, laboratory diagnosis and fundamental research. In these high sensitivity analyses, it is critical that factors which could lead to spurious changes in the measured output (optical response) of the optical sensor/biosensor be carefully controlled or referenced out. The factors which could lead to these spurious changes include, for example, temperature changes, solvent effects, bulk index of refraction changes, and nonspecific binding. The factor which is of interest in this particular discussion is the changing of the temperature.
The use of a standardized multiwell plate in these types of analyses is advantageous because it allows known automated high throughput screening (HTS) systems and known manual fluid handling systems to be used in conjunction with the “special” optical sensors. The most desirable standardized formats are the 96 multiwell plate (9 mm specimen spacing), the 384 multiwell plate (4.5 mm specimen spacing), and the 1536 multiwell plate (2.25 mm specimen spacing). All of these multiwell plates cover the same rectangular area of roughly 130 mm×85 mm. However, the use of the standardized multiwell plate (or any of the other aforementioned multi-vessel systems) can be problematic since it can be difficult to control their temperature profile because their inner wells are not able to adapt as quickly as their outer wells when there is a change in the ambient temperature.
Plus, if the multiwell plate is filled for example with water, then the well contents are going to evaporate at different rates which also makes it difficult to control the temperature profile of the multiwell plate. For example, if the multiwell plate is placed in calm ambient air in an open condition (without a cover), the peripheral regions will evaporate much more quickly than the middle regions, because the air above the wells on the edges is not saturated with water vapor as quickly as the air above the middle wells. As a consequence, these outer wells cool off more quickly due to what is known in this field as evaporation cold. This effect is also present, although quantitatively reduced, if the multiwell plate is provided with a cover.
The liquid handling devices and storages facilities can also adversely affect the temperature profile of the multiwell plate. In particular, when the liquid handling device (pipetting device) is used to transfer liquid onto a target multiwell plate it first takes up liquid from a source vessel (which is open for at least a short time) and then dispenses this liquid onto the target multiwell plate. As a result, the liquid handling device partially transfers to the target plate the temperature profile of the source plate. If the source plate is re-filled by pumps from a supply (bottle, tank, etc.), then considerable temperature profiles may be expected, especially if the source plate is filled through one single inlet opening.
In the past, it has been assumed that the use of incubators to heat the multiwell plates would solve these temperature related problems. Probably, the most widely used automatic incubators are made by Kendro/Liconic and Tomtec which are described in U.S. Pat. Nos. 6,129,428 and 6,478,524 (the contents of which are incorporated by reference herein). In these incubators, the multiwell plates are stored in stacked arrangements such that they are freely accessible from below and can thus be transported into-and-out of the incubators by a shovel-like handler. In addition, the stacked arrangements can be arranged on a support plate which continuously rotates to ensure a better (more homogeneous) temperature of the multiwell plates. Moreover, these incubators can incorporate a blower which is used to provide a not very well-defined intermixing of the air by which the multiwell plates can be further temperature-controlled. Unfortunately, in such incubators, temperature gradients of several degrees is still detectable across the diagonal of a multiwell plate. Also, in these incubators where the temperature control is performed by the air (more generally gas) there is a very slow temperature adjustment with the multiwell plates.
It is known from the literature that this should be able to be done better. For instance, by using a temperature balancing body that contacts the full surface of the bottom of the multiwell plate, the temperature of the multiwell plate can be adjusted in a manner that is faster and more homogeneous (see, DE 3441179 C2 and U.S. Pat. No. 5,459,300 the contents of which are incorporated by reference herein). However, the literature does not describe how the multiwell plates throughput per time unit in a screening system and the temperature balance of those multiwell plates can be suitably realized especially when a screening system is going to be operating at it's sensitivity limit. This problem and other problems are solved by the screening device and method of the present invention.